RNAs that help each other assemble are more effective than selfish replicators.

Origin-of-life researchers have made great progress in creating RNA molecules with interesting biochemical activities, but they haven't yet managed to create a molecule that can fully replicate itself, an item that's considered to be the critical step that could get evolution, and thus life itself, started. But a paper published in this week's edition of Nature suggests we may be thinking about things a bit wrong. They show that it's possible to have a population of distinct RNAs that can cooperate to catalyze reactions that expand the population. And, if you mix them together, the cooperative molecules will outcompete any selfish replicators.

In a way, the difference between thinking in terms of individuals and populations mirrors a debate that has gone on for decades in the evolutionary biology community. At some levels, you can think of evolution in terms of individuals competing against their peers, and each new mutation will probably start out in a single individual. But, to have an appreciable impact, that mutation will have to spread within a population. It's also possible for populations to undergo evolutionary selection as a group, as they cooperate to compete against other groups from the same or different species.

Now, it looks like arguments over individual vs. group selection may extend to the molecular realm.

To look at how molecules can cooperate, the authors of the new paper worked with a remarkable RNA enzyme (ribozyme). Normally, this acts as a single molecule, 200 bases long. But it can be broken up into a number of parts and, as long as the breaks are in the right places, the molecule can repair itself. As long as the sequence at the breaks matches, it can also repair completely separate molecules. This works because the sequence of bases at the breaks are able to pair with a short sequence that is in the catalytic site of the ribozyme.

But the researchers realized that, if you change the sequence of bases in the catalytic site, the ribozyme can start repairing breaks at a different matching sequence. To put this in terms of bases, a ribozyme with the sequence GAG in its active site can repair breaks at the sequence CUC, because G pairs with C, A with U. But, change the sequence to GCG, and it will start repairing breaks at CGC.

How do you get this ribozyme to cooperate? Create one set of molecules that have breaks at one sequence, but can repair a different one. Then, create a second set that can repair the break on the first, but contains breaks that only the first can repair. On their own, either molecule would be largely dead. But, mix them together, and each would repair the other.

In fact, the authors created a population of three sets of molecules, each split in half. None could repair themselves, but all of them could repair one other set of molecules. Throw them together in a tube, and a population of three full-length ribozymes quickly emerged. In fact, this population would emerge even when one of the three molecules was "selfish," meaning it could either repair itself or a separate molecule.

To test how effective this cooperative catalysis was, the authors created a large population of molecules with the middle base of both the catalytic and break sequence randomized—every potential combination of break and catalytic site were present. Although selfish replicators that repaired themselves were common by a half-hour into the reaction, as time went on, cooperative networks began to dominate. By four hours, they were clearly more common than selfish replicators.

The team went on to show that even more complex networks are possible. In one case, the authors kept adding more random fragments to the reaction every hour. By eight hours, one of their samples included a network of nine active ribozymes, each of which could catalyze a reaction that repaired at least one other molecule within the network. They also created a ribozyme with four breaks, and showed that pairs of these with the appropriate sequences could also repair each other. Thus, even more complex networks should be possible.

The work is significant in a couple of ways. We've known for a while that it's possible to spontaneously form small RNA molecules, but most of the interesting ribozymes are much larger. These molecules demonstrate that you don't actually need a large, intact molecule to create a catalytic activity, and that the activity itself can potentially build larger molecules.

But the more significant finding is that it's possible to create a population that, as a whole, performs better than a single selfish replicator, even though many of its members catalyze different reactions. In doing so, it suggests that some of the more complex ideas of population genetics might apply to the RNA world—the authors even conclude their paper by using the phrase "molecular ecological succession." By changing the way people think about the problem, the paper may help foster progress in the field that goes well beyond the use of these specific molecules.